Usually, with solid oral dosage forms all excipients have to be homogenously distributed therein. Whereas typically solid excipients, irrespective of their relative amounts, can be homogenously mixed without facing any significant problems, it is rather critical to homogenously distribute liquids, more in particular relatively small amounts of an oil, in a solid mixture. For some solid formulations it might even be desirable to homogenously incorporate therein less than 1%, even less than 0.5 wt-% of an oil, e.g. vitamin E. However, it is not always feasible to melt the entire formulation in order to achieve homogenous mixing.
According to U.S. Pat. No. 4,603,143 a free-flowing vitamin E or vitamin E acetate containing powder is obtained by adding a liquid form of a vitamin E or vitamin E acetate in an amount sufficient to yield a content of about 40 to about 60 wt-% to a silicon-containing adsorbent in the form of substantially discrete non-amorphous agglomerates. At least 50% of said agglomerates have to have a minimum length, width, or both of 300 microns. This process does not require any spray-drying technique. It has been observed that the mixing process as such generates some heat while the liquid vitamin is adsorbed on the surface of the adsorbent powder thereby improving the absorption process.
In GB 1,147,210 problems associated with spray-drying processes in the preparation of dry, finely divided, solid, fat-soluble, vitamin-active products shall be overcome by first preparing a colloidal solution from cold water dispersible, non-gelling colloidal material and water, dispersing therein a water-insoluble, fat-soluble, vitamin-active composition to form a first dispersion, then dispersing said first dispersion in a water immiscible dispersing medium whereby a second dispersion is formed. In the following water is extracted at a temperature in the range from −10 to 0° C. by use of a water extracting agent until said colloidal material solidifies, whereby finely divided, solid particles, containing said water-insoluble, fat-soluble vitamin-active composition dispersed therein is formed. Then, at a temperature in the range from −10 to 0° C. solid particles are separated from said dispersing medium. Finally, substantially all residual moisture is removed from said solid particles. According to GB 1,147,210 with vitamin E as the fat-soluble vitamin-active component a finely divided product is obtained having a particle size distribution such that 91.5 wt-% of a product is in the range from −30 mesh to +120 mesh (US screen sizes).
In EP 229 652 B1 it is disclosed that dry potency stabilized, particulate, free-flowing tocopherol compositions which contain 20 to 60 wt-% of tocopherol in its free tocopherol form and 40 to 80 wt-% of a carrier, based on the total weight of carrier and tocopherol, can be obtained by forming an emulsion or slurry therefrom which in addition has to contain a potency stabilizer in an amount from 2 to 50 wt-% based on the total weight of stabilizer and tocopherol. This emulsion or slurry is subjected to spray-drying. Suitable potency stabilizers are reported to be ascorbic acid, a mixture of ascorbic acid and cysteine and a mixture of citric acid and cysteine. The preferred particle size of the spray-dried product lies in the range from 200 to 500 μm.
According to U.S. Pat. No. 4,892,889 a spray-dried vitamin powder suitable for the preparation of direct-compression vitamin tablets is obtained by spray-drying in a conventional spray-dryer a mixture comprising a fat-soluble vitamin, gelatin having a bloom number between 30 and 300, a water-soluble carbohydrate, and an effective amount of water to permit spray-drying. The final powder shall contain from 20 to 60 wt-% of the fat-soluble vitamin, from 6 to 46 wt-% of the gelatin, and an effective amount of said carbohydrate to prevent extrusion.
In U.S. Pat. No. 4,262,017 a process for the preparation of a vitamin E dry powder having a high content of vitamin E is disclosed which requires dissolving sodium or potassium caseinate in a very specific residual liquor from the production of lactose. The obtained solution has to be mixed with oily vitamin E acetate in a pressure homogenizer to form a dispersion which is subjected to spray-drying to form a powder containing lactose, sodium or potassium caseinate and vitamin E acetate. The final powder product has to contain from 10 to 60 wt-% of vitamin E acetate.
In WO 96/03979 A1 solid dosage forms exhibiting controlled release of an active ingredient can be obtained by spray drying or spray congealing if an atomizing device is employed which uses mechanical vibrations of resonant metal elements or nozzles. According to a preferred embodiment, the resonant metal element comprises an appropriately shaped sonotrode. With the method according to WO 96/03979 A1 the overall dimension of the equipment necessary to obtain solid dosage forms with controlled release can be minimized.
Document WO 98/35655 A2 discloses a process for incorporating at least two incompatible active ingredients into a solid dosage form in such a manner that these ingredients are not in contact with each other. This is accomplished by first distributing the first active ingredient into a lipid or lipoid component having a higher melting point and subsequently mixing the second active ingredient with said granulated higher melting lipid which contains the first active ingredient and with another lipid or lipoid component having a lower melting point. The weight ratio of the higher melting lipid and the lower melting lipid has to be in the range from 1:5 to 5:1. It is described that the first active ingredient can be incorporated into the higher melting lipid or lipoid component by way of spray congealing.
According to WO 99/12864 A2 stearic acid wax, glyceryl fatty acid esters, glyceryl monostearate and lauric acid wax after having been mixed with an active pharmaceutical agent can be subjected to spray congealing. Similarly, in WO 95/17174 A1 it is disclosed to spray congeal a mixture comprising a material selected from the group consisting of C14-18 fats, C16-20 fatty acids, and C14-18 waxes, and dioctylsulfosuccinate.
With the aforementioned established procedures generally only large amounts of vitamin E or derivatives thereof can be employed. It, thus, would have been desirable to be also in the position to homogenously incorporate oily compounds such as vitamin E in rather small amounts into solid excipients used for the manufacture of tablets.
Therefore, it has been an object of the present invention to provide a process for homogenously incorporating a component being in liquid form at ambient temperature or having a waxy consistency, in particular small amounts of such a component, such as for example a waxy or, in particular, oily substance, into a solid component, in particular relatively large amounts of a solid component. The process for homogenously incorporating a liquid into a solid component is preferably also a continuous process enabling the processing of larger amount on an industrial scale. The thus obtained powder with a good, an acceptable blend uniformity (uniform distribution, preferably a relative standard deviation up to 6% (see below in example 5), of the component being in liquid form at ambient temperature or having a waxy consistency in the obtained powder) can then be used for the manufacture of a solid dosage form, in particular a solid dosage form for pharmaceutical use, such as a tablet, capsule, bead, pellet. Further, it has been an object of the present invention to provide a method for manufacturing a solid dosage form, such as for example a tablet, which comprises a component being in liquid form at ambient temperature or having a waxy consistency, in particular relatively small amounts of such a component, e.g. an oily substance, being homogeneously distributed within said solid dosage form. The thus obtained solid dosage form, in particular the tablet, has a good, an acceptable content uniformity for the said component. It has been another object of the present invention to provide a versatile basis for the production of a solid dosage form while keeping various pathways open to arrive at a final solid dosage form thereby furnishing a greater flexibility.